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J. Biol. Chem., Vol. 277, Issue 11, 9415-9421, March 15, 2002
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From the Departments of We have shown in a previous study
that desensitization and internalization of the human dopamine
D1 receptor following short-term agonist exposure are
mediated by temporally and biochemically distinct mechanisms. In the
present study, we have used site-directed mutagenesis to remove
potential phosphorylation sites in the third intracellular loop and
carboxyl tail of the dopamine D1 receptor to study these
processes. Mutant D1 receptors were stably transfected into
Chinese hamster ovary cells, and kinetic parameters were measured.
Mutations of Ser/Thr residues to alanine in the carboxyl tail
demonstrated that the single substitution of Thr-360 abolished agonist-induced phosphorylation and desensitization of the receptor. Isolated mutation of the adjacent glutamic acid Glu-359 also abolished agonist-induced phosphorylation and desensitization of the receptor. These data suggest that Thr-360 in conjunction with Glu-359 may comprise a motif necessary for GRK2-mediated phosphorylation and desensitization. Agonist-induced internalization was not affected with
mutation of either the Thr-360 or the Glu-359 residues. However, receptors with Ser/Thr residues mutated in the distal carboxyl tail
(Thr-446, Thr-439, and Ser-431) failed to internalize in response to
agonist activation, but were able to desensitize normally. These
results indicate that agonist-induced desensitization and internalization are regulated by separate and distinct serine and
threonine residues within the carboxyl tail of the human dopamine D1 receptor.
Distinct Residues in the Carboxyl Tail Mediate Agonist-induced
Desensitization and Internalization of the Human Dopamine
D1 Receptor*
,,,,,§¶, and¶
Pharmacology and
§ Medicine, University of Toronto, Toronto, Ontario M5S 1A8
and ¶ The Centre for Addiction and Mental Health, Toronto,
Ontario M5T 1R8, Canada
*
This work was supported by grants from the Canadian
Institutes for Health Research and the NIDA, National Institutes of
Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Pharmacology, University of Toronto, Medical Sciences Bldg., Rm. 4353, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-7579; Fax:
416-971-2733; E-mail: brian.odowd@utoronto.ca.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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